Wild Biotech co-founder Neta Raab

Two Church lab vets, a se­cre­tive in­sti­tute and an Is­raeli bil­lion­aire hunt for drugs in the guts of wild an­i­mals

Over the last four years, Ne­ta Raab and Ido Bachelet have re­ceived hun­dreds of padded card­board box­es con­tain­ing frozen poop from wild an­i­mals on five dif­fer­ent con­ti­nents.

The pack­ages came reg­u­lar­ly to their lab out­side Tel Aviv, sent from a squad of zo­ol­o­gists and spe­cial­ized Is­raeli army vet­er­ans who tracked enough an­i­mals to fill a Rud­yard Kipling nov­el, rush­ing to col­lect vul­ture and rhi­no and frog sam­ples with­in an hour of ex­tru­sion. Raab and Bachelet care­ful­ly opened the box­es, re­mov­ing the sam­ples from plas­tic-wrapped tubes and then us­ing spe­cial­ized mag­net­ic beads to fish out the bac­te­r­i­al DNA in­side for se­quenc­ing.

The re­sult of that ef­fort ap­peared Thurs­day in Sci­ence, where Raab, Bachelet and promi­nent Is­raeli com­pu­ta­tion­al bi­ol­o­gist Er­an Se­gal pub­lished what amounts to the largest data­base ever as­sem­bled of the mi­cro­bio­me, or gut bac­te­ria, in­side dif­fer­ent mem­bers of the an­i­mal king­dom. Sam­pling near­ly 200 an­i­mals, they doc­u­ment­ed 5,000 genomes across over 1,200 dif­fer­ent bac­te­r­i­al species, most of which had nev­er been seen be­fore.

Jack Gilbert

It’s a ma­jor sci­en­tif­ic achieve­ment, out­side ex­perts say, one that will al­low the grow­ing num­ber of re­searchers study­ing the mi­cro­bio­me in­side par­tic­u­lar an­i­mals, in­clud­ing hu­mans, to fit their find­ings in­to a broad­er con­text. But for Raab and Bachelet, two vet­er­ans of the George Church Lab, it’s al­so a vast trove of ge­net­ic in­for­ma­tion that could be mined for new drugs on a long list of dis­eases.

They’ve launched a com­pa­ny, Wild Biotech, to be­gin turn­ing the genes they found in­to ther­a­pies for im­muno­log­i­cal, in­flam­ma­to­ry and gas­troin­testi­nal con­di­tions. The idea is that these bac­te­ria have, over mil­lions of years, evolved pro­teins to car­ry out a wide range of unique func­tions for their hosts. Tap­ping and en­gi­neer­ing those pro­teins could help cor­rect prob­lems in hu­mans.

“This re­source re­al­ly does cre­ate a plat­form — a spring­board if you will — to ac­cel­er­ate re­search, to help us lever­age the mi­cro­bio­me in treat­ing dis­ease, im­prov­ing health, restor­ing ecosys­tems,” says Jack Gilbert, a mi­cro­bial ecol­o­gist at UC San Diego who is not in­volved in the re­search or the com­pa­ny.

Time­wise, he adds, bac­te­ria have a leg up on any med­i­c­i­nal chemist in a drug lab. “If you think about it, na­ture has been ex­per­i­ment­ing with vari­ants in mi­cro­bial chem­istry for bil­lions of years,” he says. “That’s a lot of ex­per­i­men­ta­tion — way more than any hu­man en­deav­or could hope to achieve.”

Dan Littman

Wild Biotech joins the long list of com­pa­nies that have raised bil­lions to lever­age sci­en­tists’ grow­ing un­der­stand­ing of the hu­man mi­cro­bio­me in­to new drugs for can­cer or in­fec­tious dis­ease. Those ef­forts, though, have large­ly fo­cused on giv­ing peo­ple tablets con­tain­ing strains of liv­ing bac­te­ria from hu­mans, re­ly­ing on the con­flu­ence of hun­dreds of dif­fer­ent genes to re­store a healthy im­mune sys­tem.

In try­ing to tap an­i­mal mi­cro­bio­mes and iso­late in­di­vid­ual pro­teins, Raab and Bachelet will have to show a deep­er un­der­stand­ing of the bac­te­ria and the func­tion of the genes they un­cov­ered. They say they have that tech­nol­o­gy and they’ve re­ceived an em­i­nent backer in Is­raeli bil­lion­aire Mar­ius Nacht, but so far, it re­mains un­pub­lished and un­proven.

“My guess is that there’s gonna be a lot of valu­able med­i­c­i­nal in­for­ma­tion in there,” says Dan Littman, a pro­fes­sor of mol­e­c­u­lar im­munol­o­gy at NYU and co-founder of the mi­cro­bio­me biotech Vedan­ta. “But it’s go­ing to take an enor­mous amount of work to go from here to the next step of mak­ing a valu­able prod­uct.”

A hye­na cre­at­ing a mi­cro­bio­me sam­ple in Ugan­da. Re­searchers will col­lect it with­in the hour (Gal Zanir)

Click on the im­age to see the full-sized ver­sion

A se­cre­tive Is­raeli in­sti­tute with some bird ques­tions

Wild Biotech grew out of work Raab, Bachelet and their third co­founder, Doron Levin, con­duct­ed at a small in­sti­tute in Re­hovot, Is­rael called Aug­man­i­ty. Bachelet did his post­doc at the Church lab, where he start­ed mak­ing a name in a field of nan­otech­nol­o­gy called DNA origa­mi, and he says he found­ed Aug­man­i­ty af­ter leav­ing acad­e­mia to back am­bi­tious sci­en­tif­ic projects. But he of­fered no oth­er de­tails, in­clud­ing what oth­er work they do or how many peo­ple work there.

“We’re a very stealthy or­ga­ni­za­tion,” Bachelet says, point­ing me to a sin­gle-page web­site that was of­fline at the time. “There’s no sign on the build­ing, there’s no sign on the door.”

Raab, a for­mer stu­dent and now Wild’s CEO, joined Aug­man­i­ty af­ter her own stint at the Church lab, hop­ing to help build Is­rael’s biotech scene.

The mi­cro­bio­me project arose out of sev­er­al ideas they had about birds: Is­rael is a land­ing spot for bil­lions of birds mi­grat­ing be­tween Africa and Eu­rope — could they sam­ple their drop­pings and warn coun­tries of the path­o­gen­ic bac­te­ria they car­ry? They al­so won­dered about the mi­cro­bio­mes in vul­tures and oth­er scav­engers. These an­i­mals eat rot­ting flesh, so they need to evade or with­stand the tox­ins in the bac­te­ria that grow on corpses. Did they use their own mi­cro­bio­mes to do so?

Soon, they were ask­ing about all sorts of dif­fer­ent an­i­mals and how they sur­vived con­di­tions hu­mans nev­er en­counter. “So the idea was born from many dif­fer­ent small ques­tions,” Raab says. “But at some point, we kind of had an epiphany.”

Raab worked with ex­perts from the Is­raeli sa­fari and IDF spe­cial­ists to track an­i­mals in Hun­gary, Ugan­da, the Falk­land Is­lands, Mada­gas­car, Aus­tralia and Is­rael. They used drones to fol­low an­i­mals and teamed with guides and rangers to track them by foot and ve­hi­cle. They put up nets to trap and band birds. They board­ed in­flat­able boats to trail whales off the Falk­land Is­lands, skim­ming sam­ples on the wa­ter’s sur­face.

Along with the fe­cal sam­ple, track­ers al­so logged de­tails about the in­di­vid­ual an­i­mal and lo­ca­tion. Oth­er re­searchers have looked at a wide range of cap­tive an­i­mals, but Raab want­ed wild an­i­mals, point­ing to re­search that cap­tiv­i­ty can change or even crip­ple an an­i­mal’s mi­cro­bio­me.

“It changes their ca­pac­i­ty to re­turn to na­ture,” she says. “And we re­al­ly want­ed to look for the spe­cif­ic fea­tures that en­able them to re­al­ly sur­vive in the hos­tile and harsh en­vi­ron­ments.”

To an­a­lyze the sam­ples af­ter they ar­rived in Is­rael, Bachelet and Raab reached out to Se­gal, a pi­o­neer in com­pu­ta­tion­al ge­net­ics who some­times worked on the hu­man mi­cro­bio­me. The two labs broke the DNA they ex­tract­ed — a tan­gle of strands from all the var­i­ous mi­crobes in a giv­en fe­cal sam­ple called a “metagenome” —  in­to small pieces that can be read by a se­quencer. The se­quencer spits out an in­com­pre­hen­si­ble jum­ble of frag­ments from hun­dreds or thou­sands of dif­fer­ent bac­te­ria. But by look­ing for places where the dif­fer­ent frag­ments over­lap, the re­searchers can stitch com­plete genomes back to­geth­er.

They can then tag in­di­vid­ual genes by look­ing for rec­og­niz­able pat­terns. Every gene, for ex­am­ple, starts and ends with string of let­ters called a “start” and “stop” codon.

“A metagenome is like an in­com­plete jig­saw puz­zle thrown on the floor,” says Gilbert, the UCSD re­searcher. “What they’ve done is take those puz­zle pieces and start to piece them to­geth­er.”

Sur­pris­ing in­sights

The work im­me­di­ate­ly brought sur­pris­es. David Zee­vi, a PhD stu­dent at Se­gal’s lab who worked on the metagenome analy­sis, says bac­te­ria that live on land and in the sea gen­er­al­ly have sim­i­lar genomes. So he was shocked by how much the mi­cro­bio­mes could vary be­tween species and how many new genes ap­peared.

“They have such a huge di­ver­si­ty, huge po­ten­tial of new mi­cro­bial genes,” says Zee­vi, who is now an in­de­pen­dent fel­low at Rock­e­feller about to launch his own mi­cro­bio­me lab at the Weiz­mann In­sti­tute. “What are the se­lec­tive pres­sures, in terms of evo­lu­tion, that led to some­thing like this?”

For Bachelet and Raab, though, the big ques­tion is whether they can trans­late the data­base in­to drugs. They be­gan link­ing the genes they found to traits in the pa­per, show­ing for ex­am­ple dif­fer­ences be­tween car­ni­vores and her­bi­vores that might give meat-eaters en­hanced abil­i­ties to com­bat tox­ic bac­te­ria.

As a proof-of-con­cept, they syn­the­sized one pro­tein found in grif­fon vul­tures’ mi­cro­bio­me they be­lieved helped it com­bat the dead­ly synapse-cut­ting poi­son bot­u­linum tox­in A. It turned out that the pro­tein ac­tu­al­ly sped up the tox­in’s ef­fect — part of what the re­searchers be­lieve is a cas­cade of en­zymes grif­fons use to clear it.

Bot­u­linum tox­in A is al­so the key in­gre­di­ent in Ab­b­Vie bil­lion-dol­lar Botox. Per­haps, Bachelet says, you can use the grif­fon pro­tein to cre­ate a fast-act­ing Botox, or “Su­per-Botox.” “That’s al­ready a mar­ket,” he says.

Naa­ma Ge­va Za­torsky

Naa­ma Ge­va-Za­torsky, who runs a sys­tems bi­ol­o­gy lab at the Tech­nion, agreed the tox­in pro­vid­ed a good test case, adding that she’d now like to see larg­er work on col­lect­ing, study­ing and freez­ing an­i­mal mi­cro­bio­me sam­ples, as re­searchers have done with hu­man mi­cro­bio­mes.

“This is a pure­ly beau­ti­ful study!” she said in an email. “Trans­lat­ing to med­i­cine is to­tal­ly fea­si­ble.”

Not every­one is con­vinced, though. David Berry, a part­ner at Flag­ship who played a piv­otal role in found­ing the mi­cro­bio­me biotechs Seres Ther­a­peu­tics, Evelo Bio­sciences and In­di­go Agri­cul­ture, says their work brought ma­jor in­sights in­to an un­der-ex­plored area. In the past, though, he says re­searchers have strug­gled to iso­late in­di­vid­ual genes that give a par­tic­u­lar gut bac­teri­um its im­pact.

David Berry

Of­ten­times, sci­en­tists would see two strains of the same species, one that has a pro­found ef­fect on its host and one that doesn’t. But when they tried to com­pare the two genomes to find the dif­fer­ence, they would find mil­lions of dif­fer­ences — on the same scale that sep­a­rates hu­man and ba­nanas, say, or hu­mans and fun­gi — mak­ing it im­pos­si­ble to sin­gle out a pro­tein that could be ther­a­peu­tic.

Still, he adds, some­times they found chem­i­cals pro­duced by the mi­crobes that were piv­otal.

“I wouldn’t rule out the po­ten­tial that there’s some­thing deeply im­por­tant and deeply in­sight­ful in the da­ta,” he says. “But I think there’s a whole bunch of steps that have to be tak­en to turn this in­to some­thing that can pro­duce drugs.”

A wild fu­ture 

Bachelet and Raab are now work­ing on those steps. So far they’re keep­ing most de­tails about the com­pa­ny un­der wraps. They say they have a far larg­er data­base than the one they pub­lished in Sci­ence and an AI-as­sist­ed soft­ware that can link the in­di­vid­ual genes they found to po­ten­tial im­pact par­tic­u­lar dis­or­ders.

They’re fo­cus­ing, Bachelet says, on pro­teins and func­tions you can’t find in the hu­man mi­cro­bio­me and that might of­fer new routes of ad­min­is­tra­tion or the abil­i­ty to rad­i­cal­ly al­ter the im­mune sys­tem. With bil­lion­aire Nacht’s back­ing, they’ve built a 9-per­son-team with­out hav­ing to re­ly on tra­di­tion­al VC fund­ing.

The com­pa­ny has a cou­ple lead can­di­dates from the ini­tial analy­sis and they’ll work on ex­pand­ing the plat­form and re­fin­ing the soft­ware for at least the next year, be­fore they po­ten­tial­ly need more fund­ing. In the mean­time, they’ve frozen all their old sam­ples should they need to be test­ed again or if they want to try to cul­ture in­di­vid­ual strains liv­ing in­side. It’s a one-of-a-kind re­source for the fu­ture.

“We’re heads down,” Raab says. “It’s ear­ly, still.”

BY­OD Best Prac­tices: How Mo­bile De­vice Strat­e­gy Leads to More Pa­tient-Cen­tric Clin­i­cal Tri­als

Some of the most time- and cost-consuming components of clinical research center on gathering, analyzing, and reporting data. To improve efficiency, many clinical trial sponsors have shifted to electronic clinical outcome assessments (eCOA), including electronic patient-reported outcome (ePRO) tools.

In most cases, patients enter data using apps installed on provisioned devices. At a time when 81% of Americans own a smartphone, why not use the device they rely on every day?

Launched by MIT grads, a small start­up gets $20M to back a ro­bot­ics rev­o­lu­tion in cell ther­a­py man­u­fac­tur­ing

As co-director of an experimental cellular therapy process development and manufacturing group at UCSF specializing in T cell therapies for autoimmune conditions, Jonathan Esensten has learned a lot about the challenges involved when his group hand-fashions a cell therapy. Esensten — who was a postdoc in Wendell Lim’s lab and counts the legendary Jeffrey Bluestone as a mentor — gives them all high marks at being great at what they do, but time and again there are variations in the treatments they construct.

Near­ly a year af­ter Au­den­tes' gene ther­a­py deaths, the tri­al con­tin­ues. What hap­pened re­mains a mys­tery

Natalie Holles was five months into her tenure as Audentes CEO and working to smooth out a $3 billion merger when the world crashed in.

Holles and her team received word on the morning of May 5 that, hours before, a patient died in a trial for their lead gene therapy. They went into triage mode, alerting the FDA, calling trial investigators to begin to understand what happened, and, the next day, writing a letter to alert the patient community so they would be the first to know. “We wanted to be as forthright and transparent as possible,” Holles told me late last month.

The brief letter noted two other patients also suffered severe reactions after receiving a high dose of the therapy and were undergoing treatment. One died a month and a half later, at which point news of the deaths became public, jolting an emergent gene therapy field and raising questions about the safety of the high doses Audentes and others were now using. The third patient died in August.

“It was deeply saddening,” Holles said. “But I was — we were — resolute and determined to understand what happened and learn from it and get back on track.”

Eleven months have now passed since the first death and the therapy, a potential cure for a rare and fatal muscle-wasting disease called X-linked myotubular myopathy, is back on track, the FDA having cleared the company to resume dosing at a lower level. Audentes itself is no more; last month, Japanese pharma giant Astellas announced it had completed working out the kinks of the $3 billion merger and had restructured and rebranded the subsidiary as Astellas Gene Therapies. Holles, having successfully steered both efforts, departed.

Still, questions about precisely what led to the deaths of the 3 boys still linger. Trial investigators released key details about the case last August and December, pointing to a biological landmine that Audentes could not have seen coming — a moment of profound medical misfortune. In an emerging field that’s promised cures for devastating diseases but also seen its share of safety setbacks, the cases provided a cautionary tale.

Audentes “contributed in a positive way by giving a painful but important example for others to look at and learn from,” Terry Flotte, dean of the UMass School of Medicine and editor of the journal Human Gene Therapy, told me. “I can’t see anything they did wrong.”

Yet some researchers say they’re still waiting on Astellas to release more data. The company has yet to publish a full paper detailing what happened, nor have they indicated that they will. In the meantime, it remains unclear what triggered the events and how to prevent them in the future.

“Since Audentes was the first one and we don’t have additional information, we’re kind of in a holding pattern, flying around, waiting to figure out how to land our vehicles,” said Jude Samulski, professor of pharmacology at UNC’s Gene Therapy Center and CSO of the gene therapy biotech AskBio, now a subsidiary of Bayer.

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Pascal Soriot (AstraZeneca via YouTube)

Af­ter be­ing goad­ed to sell the com­pa­ny, Alex­ion's CEO set some am­bi­tious new goals for in­vestors. Then Pas­cal So­ri­ot came call­ing

Back in the spring of 2020, Alexion $ALXN CEO Ludwig Hantson was under considerable pressure to perform and had been for months. Elliott Advisers had been applying some high public heat on the biotech’s numbers. And in reaching out to some major stockholders, one thread of advice came through loud and clear: Sell the company or do something dramatic to change the narrative.

In the words of the rather dry SEC filing that offers a detailed backgrounder on the buyout deal, Alexion stated: ‘During the summer and fall of 2020, Alexion also continued to engage with its stockholders, and in these interactions, several stockholders encouraged the company to explore strategic alternatives.’

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Anand Shah (FDA)

For­mer head of FDA’s med­ical and sci­en­tif­ic af­fairs on Covid: ‘FDA has nev­er been test­ed like this’

Anand Shah has served the American public in a unique way, crisscrossing over the last two administrations between serving as an attending radiation oncologist focused on prostate cancer at NIH, serving as CMO at the Center for Medicare and Medicaid Innovation, and most recently, leading the FDA’s operations on medical and scientific affairs from within the commissioner’s office.

Shah, who stepped down from the FDA in January, caught up with Endpoints News in a phone interview on Tuesday afternoon, offering his thoughts on the agency’s latest decision to pause the J&J vaccinations in the US, and reflecting on his time at an agency during this once-in-a-lifetime pandemic.

Barbara Weber, Tango Therapeutics CEO (Tango)

It takes two to Tan­go: The biotech us­ing CRISPR to dis­cov­er new can­cer gene tar­gets rides a $353M SPAC deal to Nas­daq

Editor’s note: Interested in following biopharma’s fast-paced IPO market? You can bookmark our IPO Tracker here.

The latest biotech-SPAC deal has arrived, and it’s dancing its way to Nasdaq to the tune of several hundred million dollars.

Tango Therapeutics and its CRISPR-focused search for new cancer genes is reverse merging with Boxer Capital’s blank-check company, the biotech announced Wednesday morning. With a spotlight on three lead programs, Tango expects total proceeds to equal about $353 million in the deal, which includes the roughly $167 million held in the SPAC and an additional $186 million in PIPE financing.

Kristin Fortney, BioAge Labs CEO

An­ti-ag­ing biotech up­start plucks a drug from Am­gen's dis­card pile, piv­ot­ing from heart fail­ure to mus­cle con­di­tions

Back in April 2019, Amgen quietly shut down a Phase I trial for a drug named AMG 986. There was no safety concern; the molecule just didn’t hit the mark on helping the small band of heart failure patients who received it.

A small biotech, though, believes it would stand a chance in the burgeoning anti-aging field.

BioAge Labs has licensed AMG 986 — now renamed BGE-105 — with plans to parlay the existing IND into a quick Phase I trial teasing out the pharmacodynamic effects and set the stage for mid-stage tests focused on acute muscle indications.

UP­DAT­ED: J&J paus­es vac­cine roll­out as feds probe rare cas­es of blood clots

The FDA and CDC have jointly decided to stop administering J&J’s Covid-19 vaccine after reviewing data involving six reported US cases of a rare and severe type of blood clot in individuals after receiving the vaccine.

CDC will convene a meeting of its Advisory Committee on Immunization Practices on Wednesday to further review these cases and assess their potential significance. “FDA will review that analysis as it also investigates these cases. Until that process is complete, we are recommending a pause in the use of this vaccine out of an abundance of caution,” Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research and Anne Schuchat, Principal Deputy Director of the CDC, said in a joint statement Tuesday morning.

Patrizia Cavazzoni, new CDER director

Pa­trizia Cavaz­zoni named per­ma­nent di­rec­tor of CDER, adding to ques­tions around where Wood­cock will end up

Patrizia Cavazzoni on Monday became the permanent director of the FDA’s Center for Drug Evaluation and Research, which puts to rest the idea that Janet Woodcock, Cavazzoni’s predecessor, might return to lead CDER if she isn’t made permanent commissioner.

Woodcock, who’s currently serving as acting commissioner and principal medical advisor to the commissioner, a position she was detailed to last year, may not make the move to permanent commissioner because of lingering questions from Senate Democrats. She previously served as director of CDER since 1994. Cavazzoni took over as acting director of CDER when Woodcock moved over to Operation Warp Speed to run the therapeutics side of the Trump-era program.

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